Fig. 1: Skin blackening characteristic of septicemic plague [10].
Motivation and Background:
The Plague is an infectious disease that is caused by the bacterial organism Yersinia pestis. It is normally transmitted through fleas carrying the bacteria or through contact with an infected animal. Common symptoms of the disease include fever, chills, headache, extreme weakness, and internal bleeding. There are three clinical forms of the plague that differ in the affected area of the body [4].
Pneumonic plague is the infection of the lungs that is normally caused by inhalation of the infectious air droplets [4].
Septicemic plague results in the blackening and death of tissues and is normally due to a flea bite or contact with an infected animal [4].
Bubonic plague is the infection of the lymph nodes by Yersinia pestis that results in the swelling of the nodes. [4].
At multiple instances throughout recorded history, the plague has decimated the world’s population, such as in the case of the Black Death in which almost one third of Europe’s population was killed by the disease [8]. Through prevention efforts and the invention of modern antibiotics, the worldwide rates of the plague have declined. However, to this day the plague still remains a pressing issue in sub-Saharan Africa and Madagascar, where 95% of cases are found. Another cause of alarm is that as new species of animals become capable of carrying for the disease, the plague has been able to become endemic in the western United States as well as other rural areas in the world [5].
There are 1-2 thousand reported cases of the plague each year, but this number doesn’t account for the multitude of cases that are unreported throughout developing countries in sub-Saharan Africa. The mortality rate of the plague is around 8-10%, but some studies contend that the mortality rate may be much higher in areas where the plague is endemic [5].
Bubonic plague is a problematic disease that not only still exists in the developed world, but more importantly cripples the developing world in sub-Saharan Africa in countries such as Madagascar, Democratic Republic of Congo, Uganda, as well as countries like China, India, Vietnam, and others in the Asian continent [1,2]. Funding should be allocated to the research of bubonic plague so that inexpensive, efficient drug administration can be planned and implemented in sub-Saharan Africa [3]. Along with this, funding is needed for further research on alternatives to streptomycin that have less severe side effects. Diseases such as bubonic plague significantly stagnate the developing world and continue to persist in developed countries throughout the world.
Target Information:
Bacterial 30S Ribosomal Subunit Fig. 2: Structure of bacterial 30S ribosomal subunit in 2 opposing orientations [15].
Fig. 3: S12 protein in 30S ribosome, which the aminoglycoside Streptomycin binds to in order to hinder translation of vital proteins. [12].
Fig. 4: 16S rRNA found in 30S ribosome, which the aminoglycoside Streptomycin binds to in order to hinder translation of vital proteins [11].
Size: 30S ribosomal subunit has a weight of about 850,000 daltons
Location: Found in cytoplasm of prokaryotic cells (in this case the bacterium Yersinia pestis)
Function in a normal cell: 30S ribosomal subunit binds to the larger 50S subunit and mRNA in order to form the complex that is the bacterial ribosome. This is responsible for producing the proteins vital to the growth and functioning of Yersinia pestis.
Drug Information:
Schematic figure of drug: Fig. 4: 2D structure of Streptomycin molecule [7].
Streptomycin falls under the category of an aminoglycoside antibiotic. The mechanism behind aminoglycosides involves binding to the 16S rRNA and S12 protein in the bacterial 30S ribosomal subunit that leads to the t-RNA misreading mRNA template sequences, leaving the bacterium unable to synthesize proteins vital to its growth [7].
Formula: C21H39N7O12 [7]
Formula: C21H39N7O12 [7]
Molecular weight: 581.57406 daltons [7]
CAS Number: 57-92-1 [7]
Delivery method: Intramuscular injection (IM) [6]
Side effects: Some side effects of Streptomycin includes black, tarry stools, burning itchiness, chest pain, chills, clumsiness, cough, dizziness, fever, large, hive-like swelling (on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs), nausea, painful or difficult urination, unusual bleeding or bruising, sore throat, and general weakness of the body. May lead to hearing loss or kidney problems [14].
Other names: Streptamycin sulfate, D-Streptamine, O-2-deoxy-2-(methylamino)-α-L-glucopyranosyl-(1→2)-O-5-deoxy-3-C-formyl-α-L-lyxofuranosyl-(1→4)-N,N1-bis(aminoiminomethyl)-,sulfate (2:3) (salt) by IUPAC [7].
Maker or company: X-Gen Pharms [7].
Is it patented? Yes [9].
Clinical Trials Info: In recent years the Center for Disease Control began conducting a study in Madagascar that compares the effectiveness and safety of streptomycin, the standard drug used when treating the plague, with the drug gentamicin, which is another treatment for the plague. The hypothesized outcome is that gentamicin may be equal in efficacy for treating the plague disease, but it will have less severe side effects [1,13].
Origin: Scientist Selman A. Waksman lead a laboratory in which one of his students, Dr. Schatz, isolated streptomycin from the bacteria Streptomyces griseus that he collected from a soil sample. Waksman arranged to have the bacteria tested and found that it cured tuberculosis as well as the Plague, diseases that at the time the recently discovered penicillin could not cure. He arranged for a patent between him, Dr. Schatz, and Rutgers University in which he and Rutgers University received large sums of money, and Dr. Schatz received none. Dr. Waksman began to exclude mentioning Dr. Schatz when it came to recognition for the drug’s discovery. Dr. Schatz sued and won the title of co-discoverer, but in 1952 only Dr. Waksman was awarded the Nobel Prize for its discovery, as the Nobel committee deemed Dr. Schatz to be a lab assistant [9].
Alternatives to this drug: An alternative to Streptomycin is the bactericidal drug Levoflocaxin, as well as Gentamicin [4].
Miscellaneous: Other uses: Streptomycin is effective in treating diseases such as tuberculosis, tularemia, endocarditis, and Mycobacterium avium-intracellulare infection [14].
References:
1. Eisen, R. J.; Griffith, K. S.; Borchert, J. N.; MacMillan, K.; Apangu, T.; Owor, N.; Acayo, S.; Acidri, R.; Zielinski-Gutierrez, E.; Winters, A. M.; Enscore, R. E.; Schriefer, M. E.; Beard, C. B.; Gage, K. L.; Mead, P. S., Assessing human risk of exposure to plague bacteria in northwestern Uganda based on remotely sensed predictors. Am J Trop Med Hyg 2010, 82 (5), 904-11.
2. Eisen, R. J.; MacMillan, K.; Atiku, L. A.; Mpanga, J. T.; Zielinski-Gutierrez, E.; Graham, C. B.; Boegler, K. A.; Enscore, R. E.; Gage, K. L., Identification of risk factors for plague in the West Nile Region of Uganda. Am J Trop Med Hyg 2014, 90 (6), 1047-58.
6. Streptomycin (Streptomycin) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList. RxList, http://www.rxlist.com/streptomycin-drug.htm
Disease/Drug of interest:
The PlagueFig. 1: Skin blackening characteristic of septicemic plague [10].
Motivation and Background:
The Plague is an infectious disease that is caused by the bacterial organism Yersinia pestis. It is normally transmitted through fleas carrying the bacteria or through contact with an infected animal. Common symptoms of the disease include fever, chills, headache, extreme weakness, and internal bleeding. There are three clinical forms of the plague that differ in the affected area of the body [4].
Pneumonic plague is the infection of the lungs that is normally caused by inhalation of the infectious air droplets [4].
Septicemic plague results in the blackening and death of tissues and is normally due to a flea bite or contact with an infected animal [4].
Bubonic plague is the infection of the lymph nodes by Yersinia pestis that results in the swelling of the nodes. [4].
At multiple instances throughout recorded history, the plague has decimated the world’s population, such as in the case of the Black Death in which almost one third of Europe’s population was killed by the disease [8]. Through prevention efforts and the invention of modern antibiotics, the worldwide rates of the plague have declined. However, to this day the plague still remains a pressing issue in sub-Saharan Africa and Madagascar, where 95% of cases are found. Another cause of alarm is that as new species of animals become capable of carrying for the disease, the plague has been able to become endemic in the western United States as well as other rural areas in the world [5].
There are 1-2 thousand reported cases of the plague each year, but this number doesn’t account for the multitude of cases that are unreported throughout developing countries in sub-Saharan Africa. The mortality rate of the plague is around 8-10%, but some studies contend that the mortality rate may be much higher in areas where the plague is endemic [5].
Bubonic plague is a problematic disease that not only still exists in the developed world, but more importantly cripples the developing world in sub-Saharan Africa in countries such as Madagascar, Democratic Republic of Congo, Uganda, as well as countries like China, India, Vietnam, and others in the Asian continent [1,2]. Funding should be allocated to the research of bubonic plague so that inexpensive, efficient drug administration can be planned and implemented in sub-Saharan Africa [3]. Along with this, funding is needed for further research on alternatives to streptomycin that have less severe side effects. Diseases such as bubonic plague significantly stagnate the developing world and continue to persist in developed countries throughout the world.
Target Information:
Bacterial 30S Ribosomal SubunitFig. 2: Structure of bacterial 30S ribosomal subunit in 2 opposing orientations [15].
Fig. 3: S12 protein in 30S ribosome, which the aminoglycoside Streptomycin binds to in order to hinder translation of vital proteins. [12].
Fig. 4: 16S rRNA found in 30S ribosome, which the aminoglycoside Streptomycin binds to in order to hinder translation of vital proteins [11].
Size: 30S ribosomal subunit has a weight of about 850,000 daltons
Location: Found in cytoplasm of prokaryotic cells (in this case the bacterium Yersinia pestis)
Function in a normal cell: 30S ribosomal subunit binds to the larger 50S subunit and mRNA in order to form the complex that is the bacterial ribosome. This is responsible for producing the proteins vital to the growth and functioning of Yersinia pestis.
Drug Information:
Schematic figure of drug:
Fig. 4: 2D structure of Streptomycin molecule [7].
Streptomycin falls under the category of an aminoglycoside antibiotic. The mechanism behind aminoglycosides involves binding to the 16S rRNA and S12 protein in the bacterial 30S ribosomal subunit that leads to the t-RNA misreading mRNA template sequences, leaving the bacterium unable to synthesize proteins vital to its growth [7].
Formula: C21H39N7O12 [7]
Molecular weight: 581.57406 daltons [7]
CAS Number: 57-92-1 [7]
Delivery method: Intramuscular injection (IM) [6]
Side effects: Some side effects of Streptomycin includes black, tarry stools, burning itchiness, chest pain, chills, clumsiness, cough, dizziness, fever, large, hive-like swelling (on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs), nausea, painful or difficult urination, unusual bleeding or bruising, sore throat, and general weakness of the body. May lead to hearing loss or kidney problems [14].
Other names: Streptamycin sulfate, D-Streptamine, O-2-deoxy-2-(methylamino)-α-L-glucopyranosyl-(1→2)-O-5-deoxy-3-C-formyl-α-L-lyxofuranosyl-(1→4)-N,N1-bis(aminoiminomethyl)-,sulfate (2:3) (salt) by IUPAC [7].
Maker or company: X-Gen Pharms [7].
Is it patented? Yes [9].
Clinical Trials Info: In recent years the Center for Disease Control began conducting a study in Madagascar that compares the effectiveness and safety of streptomycin, the standard drug used when treating the plague, with the drug gentamicin, which is another treatment for the plague. The hypothesized outcome is that gentamicin may be equal in efficacy for treating the plague disease, but it will have less severe side effects [1,13].
Origin: Scientist Selman A. Waksman lead a laboratory in which one of his students, Dr. Schatz, isolated streptomycin from the bacteria Streptomyces griseus that he collected from a soil sample. Waksman arranged to have the bacteria tested and found that it cured tuberculosis as well as the Plague, diseases that at the time the recently discovered penicillin could not cure. He arranged for a patent between him, Dr. Schatz, and Rutgers University in which he and Rutgers University received large sums of money, and Dr. Schatz received none. Dr. Waksman began to exclude mentioning Dr. Schatz when it came to recognition for the drug’s discovery. Dr. Schatz sued and won the title of co-discoverer, but in 1952 only Dr. Waksman was awarded the Nobel Prize for its discovery, as the Nobel committee deemed Dr. Schatz to be a lab assistant [9].
Alternatives to this drug: An alternative to Streptomycin is the bactericidal drug Levoflocaxin, as well as Gentamicin [4].
Miscellaneous:
Other uses: Streptomycin is effective in treating diseases such as tuberculosis, tularemia, endocarditis, and Mycobacterium avium-intracellulare infection [14].
References:
1. Eisen, R. J.; Griffith, K. S.; Borchert, J. N.; MacMillan, K.; Apangu, T.; Owor, N.; Acayo, S.; Acidri, R.; Zielinski-Gutierrez, E.; Winters, A. M.; Enscore, R. E.; Schriefer, M. E.; Beard, C. B.; Gage, K. L.; Mead, P. S., Assessing human risk of exposure to plague bacteria in northwestern Uganda based on remotely sensed predictors. Am J Trop Med Hyg 2010, 82 (5), 904-11.
2. Eisen, R. J.; MacMillan, K.; Atiku, L. A.; Mpanga, J. T.; Zielinski-Gutierrez, E.; Graham, C. B.; Boegler, K. A.; Enscore, R. E.; Gage, K. L., Identification of risk factors for plague in the West Nile Region of Uganda. Am J Trop Med Hyg 2014, 90 (6), 1047-58.
3. Impact of plague. WHO, Weekly Epidemiological Record 2004, 79(33). http://www.who.int/csr/disease/plague/impact/en/
4. Plague. Centers for Disease Control and Prevention, http://www.cdc.gov/plague/index.html
5. Maps and Statistics. Centers for Disease Control and Prevention, http://www.cdc.gov/plague/maps/index.html
6. Streptomycin (Streptomycin) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList. RxList, http://www.rxlist.com/streptomycin-drug.htm
7. The PubChem Project. What’s new in PubChem RSS, https://pubchem.ncbi.nlm.nih.gov/
8. History.com staff. Black Death. History.com, http://www.history.com/topics/black-death
9. Pringle, P. Notebooks Shed Light on an Antibiotic’s Contested Discovery. The New York Times, http://www.nytimes.com/2012/06/12/science/notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html?_r=0
10. Botelho, G. Bubonic plague reported in Michigan. CNN, http://www.cnn.com/2015/09/14/health/michigan-plague/.
11. Goodsell, D. Home of David S. Goodsell, http://mgl.scripps.edu/people/goodsell
12. PDB 2hhh gallery ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI, http://www.ebi.ac.uk/pdbe/entry/pdb/2hhh/portfolio/12?view=protein_index#ad-image-0
13. Griffith, K.; Schriefer, M., Treatment and Diagnosis of Plague. https://clinicaltrials.gov/ct2/show/nct00128466?term=streptomycin
14. streptomycin intramuscular: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD. WebMD, http://www.webmd.com/drugs/2/drug-11249/streptomycin-im/details
15. Williamson, J. R. 30S ribosome assembly. 30S ribosome assembly, http://williamson.scripps.edu/website/research/entries/2008/1/23_30s_ribosome_assembly.html